Process for preparing17alpha-acetoxy-11beta-[4-n,n(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene -3,20-dione, intermediates useful in the process , and processes for preparing such intermediates

ABSTRACT

A compound having general formula (I) in which R 1  is a member selected from the group consisting of —OCH 3 , —SCH 3 , —N(CH 3 ) 2 , —NHCH 3 , —CHO, —COCH 3  and —CHOHCH 3 ; R 2  is a member selected from the group consisting of halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl and S-acyl; R 3  is a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; R 4  is a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of —O and —N—OR 5 , wherein R 5  is a member selected from the group consisting of hydrogen and alkyl. In addition to providing the compounds of formula (I), the present invention provides methods wherein the compounds of formula (I) are advantageously used, inter alia. to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; and for contraception.

CROSS-REFERENCE TO A RELATED APPLICATION

[0001] This application claims the benefit of U.S. provisional patentapplication No. 60/173,470, filed Dec. 29, 1999, the disclosure of whichis incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates generally to steroids, and inparticular to a process for preparing17α-acetoxy-11β-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione,intermediates useful in the process, and processes for preparing suchintermediates.

BACKGROUND OF THE INVENTION

[0003] International patent application No. PCT/US 97/07373, filed Apr.30, 1997, WO 97/41145, published Nov. 6, 1997, and U.S. provisionalpatent application No. 60/016,628, filed May 1, 1996, both assigned tothe same assignee as the present application, disclose, inter alia,17α-acetoxy-11β-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dioneas an antiprogestational agent. This compound also is useful in othertreatments, e.g., to induce menses or labor, to treat diseases such asendometriosis, dysmenorrhea, and endocrine hormone-dependent tumors,uterine fibroids, and to inhibit uterine endometrial proliferation.

[0004] The '628 application discloses a method for preparing thiscompound, the method being outlined in FIG. 1 herein. As shown in FIG.1, the cyanohydrin ketal (1) was converted to the silyl ether (2) byreaction with bromomethyldimethylsilyl chloride. Subsequent treatmentwith lithium diisopropylamide gave the 17α-hydroxy-21-bromo derivative(3). Displacement of the 21-bromo substituent by acetate was effected byrefluxing with potassium acetate in acetone to produce the 21-acetate(4). Hydrolysis of the crude 21-acetate (4) by potassium bicarbonategave the 17α,21-diol (5). Ketalization of the17,21-diol-4,9-diene-3,20-dione (5) was achieved by reaction withethylene glycol and tosic acid with water being removed by in vacuoazeotropic distillation. This produced the diketal (6). Theless-hindered 21-hydroxyl group was selectively methylated withtrimethyloxonium tetrafluoroborate using1,8-bis(dimethylamino)-naphthalene as a base to provide the 21-methoxycompound (7).

[0005] Epoxidation of the 21-methoxy compound (7) with hexafluoroacetonetrihydrate and 30% hydrogen peroxide produce a 2:1 mixture of 5α,10α-and 5β,10β-epoxides (8) as evidenced by NMR. As attempts to isolate pure5α,10α-epoxide (8) were unsuccessful, the crude mixture was useddirectly on to the copper (I) catalyzed Grignard reaction, to obtain the11β-[4-(N,N-dimethylamino)phenyl] derivative (9). Hydrolysis withtrifluoroacetic acid restored the 4,9-diene-3,20-dione structure (10).Acetylation of the 17α-hydroxy compound (10) with the mixed anhydrideformed from trifluoroacetic anhydride and acetic acid afforded thedesired 19-norprogesterone compound (11).

[0006] While the method described in the '628 application issatisfactory to produce the desired compound 11, there neverthelessremains a desire to provide a process for increasing the product yield.There further exists a desire for a process that employs reagents whichneed not be used in a large excess. There further exists a desire for aprocess that uses less expensive or safer reagents or conditions.

[0007] The advantages of the present invention, as well as additionalinventive features, will be apparent from the description of theinvention provided herein.

BRIEF SUMMARY OF THE INVENTION

[0008] The present invention provides a process for preparing thecompound of formula 11, that is,17α-acetoxy-11β-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione,e.g., as shown in FIG. 2. The process of the present invention includes(a) replacing the cyanohydrin group of the compound of formula 1 with a17-β-chloroacetyl group-17-α-hydroxyl group to obtain the compound offormula 12; (b) displacing the chloro group of the compound of formula12 by an acetoxy group to obtain the compound of formula 4; (c)deacetylating the compound of formula 4 to obtain the compound offormula 5; (d) selectively ketalizing the compound of formula 5 toobtain the compound of formula 13; (e) selectively methylating the21-hydroxyl group of the compound of formula 13 to obtain the compoundof formula 14; (f) reducing the 20-ketone group of the compound offormula 14 to obtain the compound of formula 15; (g) epoxidizing thecompound of formula 15 to obtain the 5α,10α-compound of formula 16; (h)introducing a N,N-dimethylaminophenyl group at the 11β-position andconcomitantly opening the epoxide ring of the compound of formula 16 toobtain the compound of formula 17; (i) deketalizing the compound offormula 17 to obtain the compound of formula 18; (j) selectivelyoxidizing the 20-hydroxyl group of the compound of formula 18 to aketone group to obtain the compound of formula 10; and (k) acetylatingthe compound of formula 10 to obtain the compound of formula 11.

[0009] The process of the present invention has one or more advantages,e.g., it employs smaller quantities of or less expensive solvents and/orreagents. The process involves intermediates, reagents, or byproductswhich are relatively safe to handle and to dispose of, and/or that aremore efficiently used in the synthesis of the compound of formula 11.The process also provides the desired final compound as well asintermediates in relatively high quantities and purity levels. Forexample, an overall yield of from about 5 to about 6 percent or more canbe achieved in preparing the compound of formula 11 starting from thecompound of formula 1 using the process of the present invention. Theprocess also involves purification methodologies that are easier topractice in a large scale compared to methods such as chromatography ordistillation methodologies used heretofore. The process further involvesless toxic reagents. One or more intermediates can be isolated uponevaporation of volatile solvents followed by aqueous precipitation. Theprocess is less labor intensive and is scalable.

[0010] The present invention further provides novel intermediates usefulin preparing the compound of formula 11. These intermediates include thecompounds of formulae 12-18. The present invention further providesprocesses for preparing these intermediates. The present inventionfurther provides a process for selectively oxidizing the secondaryalcohol group of a composition containing secondary and tertiary alcoholgroups. The selective oxidation process comprises treating thecomposition with a haloxybenzoic acid.

[0011] While the invention has been described and disclosed below inconnection with certain preferred embodiments and procedures, it is notintended to limit the invention to those specific embodiments. Rather itis intended to cover all such alternative embodiments and modificationsas fall within the spirit and scope of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 sets forth a process for preparing the compound of formula11 as described in application No. 60/016,628.

[0013]FIG. 2 sets forth a process for preparing the compound of formula11 in accordance with a preferred embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0014] In one aspect, the present invention provides a process forpreparing the compound of formula 11 generally, and preferably inaccordance with the schematic shown in FIG. 2.

[0015] The starting material, the cyanohydrin compound of formula 1, canbe obtained commercially, for example, from Davos Chemical Inc. in NewJersey. In accordance with a preferred embodiment of the invention, thestarting material is first reacted withchloro(chloromethyl)dimethylsilane to form a 17-O-silylated derivativewhich is then converted to a 17-chloroacetyl compound with the17α-hydroxyl group being maintained.

[0016] The silylation reaction is preferably carried out in the presenceof at least one base to scavenge the acid by-product. Examples ofsuitable bases include tertiary amines such as trialkylamines,pyridines, and dialkylaminopyridines, as well as combinations thereof,with the preferred base being a mixture of 4-dimethylaminopyridine(DMAP) and triethylamine. Advantageously, DMAP can be used in asub-stoichiometric amount when DMAP and another base are used. Thereaction is preferably carried out in a dry solvent such as anhydroussolvent. Examples of solvents suitable for carrying out the reactioninclude tetrahydrofuran (THF), diethyl ether, acetonitrile,dichloromethane, dioxane, dioxolane, and the like, with THF being apreferred solvent. During the reaction, the reaction mixture isadvantageously maintained at a temperature of from about −78° C. toabout 0° C., and preferably at a temperature of about −78° C.

[0017] The resulting 17-O-silylated derivative is then reacted,preferably in a one-pot process, with an alkali metal dialkylamide, toconvert the cyanohydrin group to a 17α-hydroxy-17β-chloroacetyl group.The conversion of the cyanohydrin group is preferably carried out by theprocedure known as the Silicon Nucleophilic Annelation Process (SNAP).See Livingston et al., Adv. Med. Chem., 1, 137-174 (1992); Livingston etal., J. Amer. Chem. Soc., 112, 6449-50 (1990); and U.S. Pat. Nos.4,921,638 and 4,977,255. Examples of suitable alkali metals of thedialkylamide include lithium, sodium, potassium, and rubidium, withlithium being preferred. The SNAP reaction is carried out at lowtemperatures, preferably at or below about −78° C. Lithiumdiisopropylamide is a preferred reagent for the formation of α-silylcarbanion.

[0018] The SNAP reaction, it is believed, results in the formation of anα-silyl carbanion which attacks the cyano group intramolecularly toprovide an intermediate silacycle. Subsequent hydrolysis of theintermediate provides the 17β-chloroacetyl compound of formula 12 with ahydroxyl group at the 17α-position. The hydrolysis can be carried out byany suitable method, for example, by the use of an acid, preferably inexcess relative to the base employed in the reaction. Preferred examplesof suitable acids include HCl and HBr. The acid is preferably added tothe reaction mixture as a 4-Normal solution in water. By carrying outthe above reaction as a one-pot procedure in accordance with a preferredembodiment of the invention, it is possible to eliminate difficult orcumbersome isolation procedures such as chromatographic isolation of thehalomethylsilyl ether. Any problems associated with chemical instabilityof the halomethylsilyl ether can be avoided. In addition, the one-potprocedure offers increased product yield, e.g., an yield of about 95% ormore. However, it will be appreciated by those skilled in the art thatit is not essential to the process of the present invention that aone-pot procedure be utilized.

[0019] The compound of formula 12 is preferably converted to thecompound of formula 4 by displacing the chloro group with an acetoxygroup. The displacement is carried out by any suitable method, forexample, by reacting the chloro compound with an acetate such as alkalimetal acetate. The acetate is preferably employed in excess relative tothe chloro group. The reaction can be carried out by heating thecompound of formula 12 with potassium acetate in a suitable solvent,e.g., acetonitrile. The precipitated KCl is removed by filtration, andthe product isolated from the reaction mixture by distilling off thesolvent, followed by taking up the residue in a solvent such asmethylene chloride and extracting the methylene chloride solution withwater. The acetate is found in the organic phase. The acetate can berecovered by evaporating the solvent.

[0020] The compound of formula 4 is then converted to the compound offormula 5 by hydrolyzing the acetoxy group to a hydroxyl group. Thedeacetylation is carried out by hydrolyzing the compound of formula 4with a suitable hydrolytic agent, e.g., a weak base such as abicarbonate. A suitable bicarbonate is potassium bicarbonate. Thehydrolysis can be carried out by heating, preferably refluxing, amethanol solution of the compound of formula 4 with potassiumbicarbonate. The product is isolated from the reaction mixture bydistilling off the solvent, followed by taking up the residue in asolvent such as methylene chloride and extracting the methylene chloridesolution with water. The compound of formula 5 is found in the organicphase. The compound can be recovered by removing, e.g., by evaporation,the solvent. The compound of formula 5 is obtained in high yields, e.g.,an yield of about 92% or more.

[0021] The 3-ketone group of the compound of formula 5 is selectivelyketalized, leaving the 20-ketone group intact. Thus, the selectiveketalization converts the 3-ketone to a ketal group in preference to the20-ketone group. For example, at least 80% of the ketalization proceedsat the 3-position, preferably at about 83% or more, and more preferablyonly or quantitatively at the 3-postion.

[0022] The selective ketalization can be carried out by methods known tothose skilled in the art. For example, the compound of formula 5 can bereacted with a glycol such as ethylene glycol, triethylorthoformate, anda suitable catalyst, for example, an acid catalyst such asp-toluenesulfonic acid. The selective ketalization of the 3-ketone groupproceeds at mild reaction conditions, for example, at a temperature ofbelow about 30° C. An advantage of the process of the present inventionis that it eliminates the need for ketalizing the 20-ketone group, asketalization of the 20-ketone group generally involves forcingconditions such as high temperatures and pressures. The process of thepresent invention also has the advantage that it eliminates the need forthe tedious vacuum azeotropic distillation involved in the preparationof the 3,20-diketal as well as a later deketalization involving the useof trifluoroacetic acid; see, e.g., FIG. 1.

[0023] The 21-hydroxyl group of the compound of formula 13 is thenselectively methylated to form the compound of formula 14. The selectivemethylation can be carried out by any suitable method, preferably by theuse of trimethyloxonium salt such as trimethyloxonium tetrafluoroborateas the methylating agent. An advantage of this methylating agent is thatthe compound of formula 14 can be obtained in essentially quantitativeyield by the use of only four equivalents of the methylating agent perequivalent of the hydroxyl group. The stereochemistry at the 17-carbonis preserved. The selective methylation proceeds preferentially at the21-position, at least 80% at the 21-position, preferably at an yield ofabout 92% or more, and more preferably, only or quantitatively at the21-position. Any suitable solvent can be used to carry out the selectivemethylation reaction. Preferably an ether solvent, and more preferablydimethoxyethane, is used to carry out the reaction. The reaction isadvantageously carried out by using a proton sponge such as a stericallyhindered and less nucleophilic base, e.g.,1,8-bis(dimethylamino)-naphthalene (Evans, D A, Ratz A M, Huff, B E andSheppard, G S (1995), J. Am. Chem. Soc., 117, 3448-3467). The protonsponge is preferably used in excess, more preferably at about fourequivalents per equivalent of the hydroxyl group being methylated. Thereaction can be carried out at moderate or ambient temperatures, e.g.,below about 30° C., such as at about 25° C.

[0024] The 20-ketone group of the compound of formula 14 is thenprotected, e.g., by reducing it to a hydroxyl group. The reduction canbe preferably carried out by treating the compound with a hydride suchas a metal hydride, preferably lithium aluminum hydride. The resultingmajor product of the compound of formula 15 can be purified bycrystallization, e.g., from an ether such as diethyl ether, isopropylether, isobutyl ether, n-butyl ether, with diethyl ether beingpreferred. Any small amount of the second isomer that may form can bethus removed. The compound of formula 15 is obtained in good yields,e.g., greater than about 58% or more of the major isomer. As the minorisomer can be recycled (e.g., oxidized back to the compound of formula14), loss of the intermediate is minimal.

[0025] The compound of formula 15 is preferably epoxidized to obtain thecompound of formula 16. The epoxidation can be carried out by methodsknown to those skilled in the art. The epoxidation is advantageouslycarried out by reacting the compound of formula 15 with an adduct formedfrom the reaction of a halogenated ketone such as acetone and a peroxidein the presence of a weak base such as a phosphate. Any suitableperoxide may be used, including hydrogen peroxide, sodium peroxide,potassium peroxide, benzoyl peroxide, and acetyl peroxide, with hydrogenperoxide being preferred. A convenient source of hydrogen peroxide isthe 30 wt % solution in water which is available commercially.

[0026] The halogenated ketone is preferably a hexahalogenated ketone,e.g., a hexachloro-, hexabromo-, or hexafluoroacetone, withhexafluoroacetone being preferred. The phosphate can be an alkali oralkaline earth metal phosphate. A preferred example of a suitablephosphate is Na₂HPO₄. Especially preferred is the use of Na₂HPO₄ incombination with 30 wt % hydrogen peroxide solution andhexafluoroacetone. The epoxidation is carried out in a suitable solvent,e.g., a halogenated solvent. Examples of halogenated solvents includechloroform, methylene chloride, dichloroethane, trichloroethane, withmethylene chloride being a preferred solvent.

[0027] Epoxidation of the compound of formula 15 is particularlyadvantageous as the 5α,10α-epoxide can be formed in preference to theless desirable 5β,10β-epoxide. Thus, the compound of formula 16 can beprepared so that the ratio of the 5α,10α-epoxide to the 5β,10β-epoxideis greater than 2:1, and preferably 3:1 or greater. The pure5α,10α-epoxide can be advantageously obtained by trituration of themixture with ether.

[0028] The epoxide ring of the compound of formula 16 can beconcomitantly opened along with the conjugate addition of aN,N-dimethylaminophenyl Grignard reagent at the 11β-position in thepresence of a cuprous salt, e.g., cuprous chloride. The Grignard reagentcan be prepared in situ from magnesium metal, a4-halo-N,N-dimethylaniline, e.g., 4-bromo-N,N-dimethylaniline, and acrystal of iodine. The reaction can be carried out in a suitable solventsuch as an ether, preferably tetrahydrofuran.

[0029] The Grignard reaction is carried out preferably in a dry vessel.To a reaction vessel containing the desired amount of magnesium, a smallcrystal of iodine is added, and the dried solvent is added to thevessel. A few drops of 1,2-dibromoethane are added to facilitate theinitiation of the Grignard reaction. A solution of the4-halodimethylaniline is then added. The reaction mixture is then heatedto initiate the Grignard reaction, as evidenced by the bleaching ofcolor and consumption of iodine. To the reaction mixture is then addedthe cuprous salt. To the stirred mixture is added the epoxide. Thereaction mixture is quenched by the addition of an ammonium salt, e.g.,ammonium chloride or bromide, solution in water. The cuprous ion is thenoxidized. Any suitable oxidizing agent, e.g., air or oxygen, can beemployed to carried out the oxidation. The resulting compound of formula17 can be isolated by extraction into an organic medium such as ether.

[0030] The use of the purified 5α,10α form of the compound of formula 16allows the use of less amount of the valuable Grignard reagent comparedto when a crude mixture of the 5α,10α and 5β,10β-epoxides is used. Inaddition, the use of the purified 5α,10α epoxide eliminates the need fora chromatographic purification of the 11β-substituted Grignard product.

[0031] The compound of formula 17 is then deketalized to obtain thecompound of formula 18. The removal of the ethylenedioxy group can becarried out by the use of an acid such as an organic acid. A preferredorganic acid is acetic acid. The secondary alcohol, the 20-hydroxylgroup, of the compound of formula 18 which also contains a tertiaryalcohol group at C17 can be selectively oxidized to obtain the compoundof formula 10. By the selective oxidation, the 21-hydroxyl group ispreferentially oxidized, e.g., at least 80% of the oxidation takes placeat the 21-position. Preferably, the oxidation takes place only orquantitatively at the 21-position, leaving the 17α-tertiary alcoholgroup essentially intact. The selective oxidation can be carried out bythe use of a suitable oxidizing agent, e.g., a haloxyacid such as2-iodoxybenzoic acid.

[0032] The compound of formula 10 can be acetylated at the 17-positionto obtain the compound of formula 11. The acetylation can be carried outby the use of any acetylating agent, preferably a combination oftrifluoroacetic anhydride, acetic acid, and p-toluenesulfonic acid.

[0033] The following Examples further illustrate the present invention,but of course should not be construed in any way as limiting the scopeof the invention.

EXAMPLE 1

[0034] Preparation of17α-hydroxy-21-chloro-19-norpregna-4,9-diene-3,20-dione (12)

[0035] The cyanohydrin (1, 50 g, 146.43 mmol; dried over P₂O₅) wassuspended in 550 mL of dry THF and stirred mechanically at roomtemperature under nitrogen. 4-(Dimethylamino)pyridine (DMAP) (4.47 g,36.61 mmol) was added as a solid. 26.7 mL (197.68 mmol) of freshlydistilled triethylamine (TEA) (27.6 mL, 197.68 mmol) was added viasyringe followed by the addition of freshly distilledchloro(chloromethyl)-dimethylsilane (23.0 mL, 174.72 mmol). The reactionmixture was allowed to stir overnight at ambient temperature. Thin layerchromatography (TLC)(on silica; 20% acetone in methylene chloride)showed that all the starting material had been converted to the silylether.

[0036] The reaction mixture was then cooled to −78° C. and diluted withTHF (800 mL). Lithium diisopropylamide (LDA) (2.0 M in THF/heptane, 225mL, 450 mmol) was added drop wise to the reaction mixture via anadditional funnel over a period of ½ hr. Upon completion of theaddition, the reaction mixture was stirred for a period of 2 hr at −78°C. in a dry ice bath. 4 N HCl (1000 mL, 4 moles) was added via theaddition funnel, the dry ice bath was removed, and the reaction mixtureallowed to stir overnight at room temperature. TLC (silica; 50% acetonein methylene chloride) indicated that the reaction had gone tocompletion.

[0037] The reaction mixture was then cooled to 0° C. in an ice bath andneutralized by the addition of concentrated NH₄OH (270 mL, 4 mols). Themixture was transferred to a separatory funnel and extracted with EtOAc(3×). The organic fractions were washed with water (2×), and then withbrine (1×). The combined EtOAc fractions (3×) were filtered throughsodium sulfate and evaporated in vacuo. The resulting solid was taken upin hot methylene chloride/ethyl acetate (about 2 L), and the resultingsolution was filtered to remove a fine gray precipitate. Evaporation ofthe filtrate provided a yellow solid. The solid was triturated withether and collected on a Buchner funnel. The solid was then washed withadditional ether and dried overnight in vacuo to recover 40.28 g of the21-chloro compound (12) in 78.9 % yield. This material was suitable tocarry directly on to the next reaction.

[0038] A small portion of the compound was crystallized from hotisopropanol, then dried over toluene in vacuo for analysis;m.p.=191-193° C. FTIR (KBr, diffuse reflectance): V_(max) 3436, 2948,1729, 1644, 1599, 1572, 1444, 1392, 1280 ad 1223 cm⁻¹. NMR (300 MHZ,CDCl₃) : δ0.836 (s, 3H, C18-CH₃), 4.348 and 4.647 (AB, 2H, C21-CH₂,J_(AB)=16.66 Hz) and 5.691 (s, 1H, C4-CH). MS (EI) m/z (relativeintensity): 348 (M+, 100.0), 313 (32.9), 253 (67.1), 228 (54.4), 213(71.5) and 91 (55.4).

[0039] Preparation of17α-hydroxy-21-acetoxy-19-norpregna-4,9-diene-3,20-dione (4)

[0040] A suspension of the 21-chloro compound (12, 40 g, 114.66 mmol)and KOAc (117.78 g, 1.20 moles) in acetonitrile (900 mL) was stirredmechanically and brought to reflux under nitrogen. After 1 hr reaction,TLC (silica; 5% acetone in methylene chloride) indicated that thereaction had gone to completion. The reaction mixture was allowed tocool to room temperature and the precipitated KCl and the excess KOAcwere removed by filtration through a sintered glass funnel. Theacetonitrile was evaporated in vacuo, and the resulting residue wastaken up in methylene chloride and water. The mixture was transferred toa separatory funnel, the organic and the aqueous layers were allowed toseparate, and the organic layer was removed, washed with water, and thenwith brine. The combined methylene chloride extracts (3×) were filteredthrough sodium sulfate and evaporated in vacuo. The resulting paleyellow solid was dried overnight under vacuum to recover 35.35 g of thecrude 21-OAc (4) in 82.80% yield. The material (4) was of sufficientpurity to carry on to the hydrolysis reaction later.

[0041] A sample of analytical purity was obtained by crystallization ofa small amount of 4 from boiling acetone. The sample was dried undervacuum over toluene; m.p. 216-222° C. FTIR (KBr, diffuse reflectance):v_(max) 3470, 2947, 1744, 1720, 1642, 1606, 1367 and 1236 cm⁻¹. NMR (300MHZ, CDCl₃): δ0.844 (s, 3H, C18-CH₃), 2.183 (s, 3H, C21-OAc), 4.863 and5.074 (AB, 2H, C21-CH₂, J_(AB)=17.56 Hz) and 5.686 (s, 1H, C4-CH). MS(EI) m/z (relative intensity): 372 (M⁺, 86.1), 312 (74.9), 271 (74.5),253 (100.0), 213 (93.3), 162 (76.2) and 91 (57.7).

[0042] Preparation of 17α,21-dihydroxy-19-norpregna-4,9-diene-3,20-dione(5)

[0043] A suspension of the crude 21-acetate (4, 34.57 g, 92.9 mmol) in afreshly opened methanol solvent was deoxygenated by sparging withnitrogen for ½ hr. A 0.5 M aqueous solution of KHCO₃ was similarlydeoxygenated. A KHCO₃ solution (280 mL, 140 mmol=1.5×) was added to 4,and the suspension was stirred mechanistically and brought to refluxunder nitrogen, whereupon a solution formed. After ½ hr at reflux, TLC(silica; 5% isopropanol in methylene chloride) indicated that allstarting material had been converted to a single, more polar product.The reaction mixture was cooled to room temperature, then neutralized bythe addition of HOAc (8.0 mL, 140 mmol). The methanol was evaporated invacuo. Methylene chloride was added to the residue obtained, along withmore water, and the mixture was transferred to a separatory funnel. Theorganic and aqueous layers were allowed to separate. The organic layerwas separated, washed again with water, and then with brine. Thecombined methylene chloride extracts (3×) were filtered through sodiumsulfate and evaporated in vacuo. The resulting solid was dried underhigh vacuum to recover 29.20 g of a yellow solid (5) in 95.2% yield.

[0044] A small amount of 5 was crystallized from a minimum amount ofboiling methanol to afford pale yellow crystals. It was dried in vacuoat 111° C. for analysis: m.p. 197-201° C. FTIR (KBr, diffusereflectance): v_(max) 3520, 2944, 2865, 1714, 1654, 1597, 1577 and 1387cm⁻¹. NMR (300 MHz, CDCl₃): δ0.820 (s, 3H, C18-CH₃), 4.320 and 4.695(AB, 2H, C21-CH₂, J_(AB)=19.81 Hz) and 5.676 (s, 1H, C4-CH). MS (EI) m/z(relative intensity): 330 (M⁺, 100.0), 271 (37.3), 253 (54.2), 228(64.9), 213 (63.2), 74 (27.2) and 91 (43.3).

[0045] Preparation of3,3-Ethylenedioxy-17α,21-dihydroxy-19-norpregna-5(10),9(11)-dien-20-one(13)

[0046] The 17α,21-diol (5, 10.0 g, 30.29 mmol) was suspended inmethylene chloride (100 mL, freshly opened) and stirred magnetically atroom temperature under nitrogen. Freshly distilled triethylorthoformate(12.6 mL, 75.73 mmol) was added via syringe, followed by ethylene glycol(8.81 mL, 158.11 mmol). A solution formed almost immediately. Tosic acid(287 mg, 1.1 mmol) was added as a solid and stirring continued for ½ hr.At that time, TLC (silica; 5% isopropanol in methylene chloride)indicated all starting material had been converted to a single polarproduct. The reaction mixture was transferred to a separatory funnel andwashed with saturated NaHCO₃ (1×), water (1×) and brine (1×). Combinedmethylene chloride extracts (3×) were dried by filtration through sodiumsulfate and evaporated in vacuo to give a pale yellow solid. The solidwas triturated with ether, collected on a Buchner funnel, and driedovernight under high vacuum to afford 9.19 g of 13 as a pale beigepowder in 81% yield.

[0047] A small amount of material (13) was reserved, crystallized from aminimum amount of hot methylene chloride, and dried in vacuo at 111° C.to recover 198 mg of white crystals; m.p.=214-216° C. FTIR (KBr, diffusereflectance): v_(max) 3481, 3399, 3046, 2924, 2878, 2843, 1714, 1471,1389, 1368, 1263, 1229 and 1157 cm⁻¹. NMR (300 MHZ, CDCl₃): δ0.637 (s,3H, C18-CH₃), 3.985 (s, 4H, C3-OCH₂CH₂O—), 4.293 (dd, 1H, C21-CH,J₁=19.81, J₂=3.60 Hz,), 4.697 (dd, 1H, C21-CH, J₁=19.81, J₂=3.60 Hz,),and 5.567 (t, 1H, J=2.40, C11-CH═). MS (EI) m/z (relative intensity):374 (M⁺, 51.7), 356 (21.4), 297 (34.9), 169 (54.9), 99 (98.6), and 86(100). Anal. Calcd. for C₂₂H₃₀O₅.CH₂Cl₂: C, 69.93; H, 8.01. Found: C,69.94; H, 8.03.

[0048] Preparation of3,3-Ethylenedioxy-17α-hydroxy-21-methoxy-19-norpregna-5(10),9(11)-dien-20-one(14)

[0049] A suspension of the 3-ketal-17α,21-diol (13, 9.09 g, 24.27 mmol)in anhydrous 1,2-dimethoxyethane (DME) (200 mL; Aldrich, Sure-Seal) wasstirred mechanically at ambient temperature under nitrogen. ProtonSponge (15.60 g, 72.81 mmol) was added as a solid, followed by theaddition of trimethyloxonium tetrafluoroborate (10.77 g, 72.81 mmol).After stirring overnight, TLC (silica; 5% isopropanol in methylenechloride) indicated 60% conversion of starting material. A fourthequivalent of Proton Sponge (5.20 g, 24.27 mmol) was added as a solid,followed by the addition of a fourth equivalent of trimethyloxoniumtetrafluoroborate (3.59 g, 24.27 mmol). After 3 hr at room temperature,all 21-hydroxy group was completely converted to the 21-methoxy, asevidenced by TLC. EtOAc and water were added to the mixture and theresulting mixture was transferred to a separatory funnel, and theorganic and aqueous layers were allowed to separate. The organic layerwas washed with ice-cold 1 N HCl (2×), water (1×), saturated NaHCO₃ (1×)and brine (1×). The combined EtOAc extracts (3×) were dried byfiltration through sodium sulfate and evaporated in vacuo. The productobtained was dried overnight under high vacuum to give 9.34 g of a paleyellow foam (14) in 99.05% yield. Analysis of the foam 14 by TLCindicated virtually all PROTON SPONGE had been removed and the crudeproduct was of sufficiently purity to carry directly on to thesubsequent reaction. Approximately 200 mg of the product was purified byflash chromatography (5% isopropanol in methylene chloride) foranalysis. Only the fractions of highest purity were combined andevaporated to recover a colorless film (14) in 131 mg. Trituration ofthe film produced a white powder (14). The powder was dried in vacuo at80° C. to recover 98.2 mg of 14; m.p.=117-119° C. FTIR (KBr, diffusereflectance): v_(max) 3470, 3025, 2924, 2816, 1707, 1473, 1448, 1420,1360, 1268, and 1114 cm⁻. NMR (300 MHZ, CDCl₃): δ0.658 (s, 3H, C18-CH₃),3.443 (s, 3H, C21-OCH3), 3.986 (s, 4H, C3-OCH₂CH₂O—), 4.226 and 4.469(AB, 2H, C21-CH₂, J_(AB)=17.71 Hz) and 5.577 (br s, 1H, C11-CH═). MS(EI) m/z (relative intensity): 388 (M⁺, 58.4), 297 (48.6), 211 (57.4),169 (53.9), 99 (100). Anal. Calcd for C₂₃H_(32 O) ₅.H₂O: C, 70.45; H,8.33. Found: C, 70.42; H, 8.23.

[0050] Preparation of3,3-ethylenedioxy-17α,20-dihydroxy-21-methoxy-19-norpregna-5(10),9(11)-diene(15)

[0051] To a solution of the 20-ketone (14, 9.34 g, 24.04 mmol) in dryTHF (200 mL) was added LiAlH₄ (Aldrich, 1.0 M in ether, 48.08 mL, 48.08mmol). After stirring ½ hr at room temperature under nitrogen, TLC(silica; 100% acetone in methylene chloride) indicated that all startingmaterial had been converted to a an approximately 70:30 mixture of twomore polar components. The reaction mixture was cooled to 0° C. andquenched by the addition of EtOAc (15-20 mL). After several min.,saturated Na₂SO₄ solution (20 mL) was added carefully, followed by theaddition of several scoops of solid Na₂SO₄. The mixture was allowed tostir for a period of 1 hr, then filtered through a Celite filter cake ona sintered glass funnel. The resulting filtrate was transferred to aseparatory funnel, water and EtOAc were added, and the organic andaqueous layers were allowed to separate. The organic layer was removed,washed again with water, and then with brine. The combined EtOAcextracts (3×) were dried by filtration through sodium sulfate andevaporated in vacuo to recover a pale yellow foam. The foam was taken upin a minimum amount of ether (˜20 mL) and small white crystals formedalmost immediately. After allowing the ether mixture to stand overnightin the freezer, the ether was decanted. The crystals were washed withtwo additional portions of ether, then dried overnight under high vacuumto give 5.38 g of 15 as white crystals in 57.30% yield. Examination byTLC indicated that the crystals were exclusively the major product ofthe reaction.

[0052] A sample of analytical purity was obtained by recrystallizationof 200 mg of white crystals 15 from a minimum amount of hot ether with asmall amount of methylene chloride. The resulting white crystals weredried in vacuo at 56° C. to recover 115 mg of 15; m.p. 145-157° C. FTIR(KBr, diffuse reflectance): v_(max) 3546, 3410, 3043, 2932, 2892, 2828,1645, 1472, 1451, 1436, 1420, 1370, 1335, 1261, and 1108 cm⁻¹. NMR (300MHZ, CDCl₃): δ0.765 (s, 3H, C18-CH₃), 3.395 (s, 3H, C21-OCH3), 3.535(dd, 1H, C21-CH, J₁=9.76 Hz, J₂=3.00 Hz), 3.589 (dd, 1H, C21-CH, J₁=9.76Hz, J₂=6.15 Hz), 3.895 (dd, 1H, C20-CH, J₁=6.15 Hz, J₂=3.00 Hz), 3.985(s, 4H, C3-OCH₂CH₂O—) and 5.599 (br s, 1H, C11-CH═). MS (EI) m/z(relative intensity): 390 (M⁺, 6.2), 372 (1.0), 314 (1.0), 297 (100),and 211 (42.6). Anal. Calcd for C₂₃H₃₄O₅: C, 70.74; H, 8.78. Found: C,70.62; H, 8.78.

[0053] Preparation of3,3-ethylenedioxy-5α,10α-epoxy-17α,20-dihydroxy-21-methoxy-19-norpregna-9(11)-ene(16)

[0054] To a solution of hexafluoroacetone trihydrate (4.28 g, 2.71 mL,19.44 mmol) in methylene chloride (60 mL) was added solid Na₂HPO₄ (1.84g, 12.96 mmol) and 30% H_(2 O) ₂ (2.92 mL, 28.51 mmol). The reactionmixture was stirred vigorously for a period of ½ hr at 4° C. (coldroom). A chilled solution of the 17α,20-diol (15, 5.27 g, 12.96 mmol) inmethylene chloride (30 mL) was added and rinsed in with additionalmethylene chloride (30 mL). After stirring overnight in the cold room,examination by TLC (silica; 15% acetone in methylene chloride) indicatedthat all starting material had been consumed. The epoxide product wasevident in approximately a 75:25 (α:β) ratio.

[0055] The reaction mixture was transferred to a separatory funnel andwashed successively with a 10% Na₂SO₃ solution (1×), water (1×), andbrine (1×). The combined methylene chloride extracts (3×) were dried byfiltration through sodium sulfate and evaporated in vacuo to recover afoam. Trituration with ether produced 3.63 g of an off-white solid (16)in 68.9% yield. Examination by TLC indicated that it was highly purifiedfrom the mother liquors.

[0056] A small sample (about 200 mg) was purified by flashchromatography (15% acetone in methylene chloride) for analysis.Fractions of the highest purity were combined and evaporated in vacuo torecover a white crystalline solid 16. The solid was recrystallized froma minimum amount of hot 15% acetone in methylene chloride and dried invacuo at 80° C. to recover 76.5 mg of 16 as white crystals:m.p.=173-185° C. FTIR (KBr, diffuse reflectance): v_(max) 3536, 3466,3040, 2970, 2932, 2905, 2872, 2812, 1475, 1456, 1426, 1373, 1344, and1120 cm⁻¹. NMR (300 MHZ, CDCl₃): δ0.764 (s, 3H, C18-CH₃), 3.388 (s, 3H,C21-OCH₃), 3.524 (dd, 1H, C21-CH, J₁=9.91 Hz, J₂=3.00 Hz,), 3.577 (dd,1H, C21-CH, J₁=9.91 Hz, J₂=5.85 Hz,), 3.909 (s, 5H, C3-OCH₂CH₂O— andC20-CH), and 6.062 (m, 1H, C11-CH═ of 5α,10α-epoxide). MS (EI) m/z(relative intensity): 406 (M⁺, 0.9), 388 (3.1), 313 (34.0), 295 (47.9),227 (30.5), 99 (100) and 87 (42.5). Anal. Calcd for C₂₃H₃₄O₆: C, 67.96;H, 8.43. Found: C, 67.76; H, 8.46.

[0057] Preparation of3,3-ethylenedioxy-5α,17α,20-trihydroxy-11β-[4-(N,N-dimethylamino)phenyl]-21-methoxy-19-norpregn-9-ene(17)

[0058] A dry 250 mL 3-necked flask was equipped with a stirring bar, areflux condenser, and two rubber septa. Magnesium (1.18 g, 48.5 mmol)was added and the entire apparatus dried further with a heat gun, undera stream of nitrogen. The apparatus was allowed to cool slightly and onecrystal of iodine was added. After cooling completely, 20 mL of dry THFwas added, followed by the addition of one drop of 1,2-dibromoethane. Asolution of 4-bromo-N,N-dimethylaniline (8.81 g, 44.05 mmol) in THF (10mL) was added via transfer needle and rinsed with additional THF (10mL). The mixture was heated gently with a heat gun to reflux to initiatereaction (as evidenced by bleaching of color and consumption ofmagnesium) and then allowed to stir for a period of ½ hr at roomtemperature. Copper (I) chloride (480 mg, 4.85 mmol) was added as asolid and stirring was continued for a period of ½ hr. A solution of theepoxide (16, 3.58 g, 8.81 mmol) in THF (20 mL) was added via transferneedle and rinsed in with additional THF (10 mL). After stirring foranother 2 hr. at room temperature, the reaction was quenched by theaddition of saturated NH₄Cl solution (70 mL). Air was drawn through themixture for period of ½ hr with vigorous stirring. The resulting mixturewas transferred to a separatory funnel, and water and ether were added.The organic and aqueous layers were allowed to separate. The organicfraction was washed again with water (1×) and brine (1×). The combinedether extracts (3×) were dried by filtration through sodium sulfate andevaporated in vacuo to recover 7.7 g of a dark purple oil. The oil wasfiltered through a short bed of silica (125 g) on a sintered glassfunnel. Elution with ether (4×200 mL) removed all of the anilineby-products. The product was eluted with EtOAc (8×100 mL). The EtOAcwashes were evaporated in vacuo to recover a beige foam. Triturationwith pentane produced a solid. The solid was dried overnight under highvacuum to give 2.48 g of 17 as a beige powder in 53.3% yield.

[0059] A small portion (250 mg) was purified by flash chromatography (5%isopropanol in methylene chloride) for analysis. Only fractions of thehighest purity were combined and evaporated to recover a colorless gum.Trituration with pentane produced a solid. The sample was dried in vacuoat 80° C. to recover 56.9 mg of 17 as a white powder; m.p.=120-126° C.(softens). FTIR (KBr, diffuse reflectance): v_(max) 3487, 2930, 1614,1559, 1517, 1445, 1374, 1198, and 1120 cm⁻¹. NMR (300 MHZ, CDCl₃):δ0.424 (s, 3H, C18-CH₃), 2.908 (s, 6H, —N(CH₃)₂), 3.361 (s, 3H,C21-OCH₃), 3.461 (dd, 1H, C21-CH, J₁=9.76 Hz, J₂=2.79 Hz), 3.527 (dd,1H, C21-CH, J₁=9.76 Hz, J₂=6.45 Hz), 3.783 (dd, 1H, C20-CH, J₁=6.45 Hz,J₂=2.79 Hz ), 3.996 (m, 4H, C3-OCH₂CH_(2 O—),) 4.210 (d, 1H, C11β-CH,J=8.70), 6.666 (d, 2H, 3′,5′-aromatic CH, J=8.70 Hz) and 7.093 (d, 2H,2′,6′-aromatic CH, J=8.70 Hz). MS (EI) m/z (relative intensity): 527(M⁺, 15.1), 509 (14.6), 238 (6.2), 134 (32.4), 121 (100), and 99 (15.1).Anal. Calcd for C₃₁H₄₅NO₆.H2O: C, 69.77; H, 8.62; N, 2.62; Found: C,69.80; H, 8.61; N, 2.43.

[0060] Preparation of17α,20-dihydroxy-11β-[4-(N,N-dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-dien-3-one(18)

[0061] To a solution of the Grignard product (17, 2.13 g, 4.04 mmol) inTHF (5 mL) was added glacial acetic acid (78.4 g, 75 mL, 1.31 mmol),followed by the addition of water (25 mL). The clear green solutionobtained was allowed to stir overnight at room temperature undernitrogen. Examination by TLC (5% isopropanol in methylene chloride; overspotted with concentrated NH₄OH before developing) indicated that allstarting material had been converted to a single, slightly less polarproduct. The reaction was cooled in an ice bath, then neutralized by thecareful addition of concentrated NH₄OH (88 mL, 1.31 mmol) to a pH of 7.0as indicated by a pH paper. The reaction mixture was transferred to aseparatory funnel and extracted by methylene chloride (3×). The organicfractions were washed with water (1×) and brine (1×). The combinedmethylene chloride extracts were dried by filtration through sodiumsulfate and evaporated in vacuo, and dried overnight under high vacuumto recover 1.93 g of an amber foam. Trituration of the amber foam withpentane produced a solid which was dried overnight under high vacuum toyield 1.78 g of 18 as a beige powder in 94.6% yield.

[0062] A small portion (˜300 mg) of the above powder was purified byflash chromatography (15% acetone in methylene chloride) for analysis.Fractions containing the product were combined and evaporated to recover223 mg of a yellow glass. Trituration of this yellow glass with pentaneproduced a solid. The solid was dried in vacuo at 80° C. to recover 185mg of a pale yellow powder; m.p.=106° C. (softens). FTIR (KBr, diffusereflectance): v_(max) 3482, 2938, 1654, 1614, 1518, 1456, 1347, 1208,and 1125 cm⁻¹. NMR (300 MHZ, CDCl₃): δ0.496 (s, 3H, C18-CH₃), 2.911 (s,6H, —N(CH₃)₂), 3.381 (s, 3H, C21-OCH₃), 3.485 (dd, 1H, C21-CH, J₁=9.76Hz, J₂=2.85 Hz), 3.547 (dd, 1H, C21-CH, J₁=9.76 Hz, J₂=6.30 Hz), 3.805(m, 1H, C20-CH), 4.313 (d, 1H, C11β-CH, J=7.20 Hz), 5.739 (s, 1H,C4-CH), 6.660 (d, 2H, 3′,5′-aromatic CH, J=8.55 Hz) and 7.045 (d, 2H,2′,6′-aromatic CH, J=8.55 Hz). MS (EI) m/z (relative intensity): 465(M⁺, 21.6), 372 (2.4), 134 (23.5), and 121 (10.0). Anal. Calcd forC₂₉H₃₉NO₄.H₂O: C, 73.67; H, 8.48; N, 2.96. Found: C, 73.64; H, 8.44; N,2.91.

[0063] Preparation of17α-hydroxy-11β-[4-(N,N-dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione(10)

[0064] A suspension of 2-iodoxybenzoic acid (IBX, 599 mg, 2.14 mmol) inanhydrous dimethylsulfoxide (DMSO) (5.0 mL; Aldrich, Sure-Seal) wasstirred magnetically under nitrogen and warmed in an oil bath at 55-60°C. After several minutes, all of the IBX was solubilized. To the IBXsolution was added a solution of the 20-alcohol (18, 500 mg, 1.07 mmol)in DMSO (5 mL). Additional DMSO (3 mL) was used to rinse in residual 18.After a period ½ hr of reaction, approximately 70% of the 20-alcohol(18) had been converted to the 20-ketone (10), as evidenced by TLC (15%acetone in methylene chloride; aliquot was diluted in water andextracted by EtOAc). After 3 hr, there was no observable change in theconversion. The reaction mixture was transferred to a separatory funnel,diluted with water, and extracted by EtOAc (3×). The EtOAc extracts werewashed with additional water (2×) and brine (1×). The combined extractswere dried by filtration through sodium sulfate, evaporated in vacuo,and dried overnight under high vacuum to recover 600 mg of a brown film.The film product was taken up in EtOAc and filtered through silica on asintered glass funnel to remove residual DMSO and highly polarimpurities. Evaporation of EtOAc afforded 450 mg of a yellow film.Repeated trituration with hexane, with scratching and sonicating,produced a solid. The solid was dried overnight under high vacuum togive 349 mg of 10 as a yellow powder in 70.1% yield. The product wascarried directly to the next reaction without further purification. NMR(300 MHz, CDCl₃): δ0.408 (s, 3H, C18-CH₃),2.906 (s, 6H, —N(CH₃)₂), 3.454(s, 3H, C21-OCH₃), 4.245 and 4.388 (AB, 2H, C21-CH₂, JAB=17.41 Hz),4.378 (d, 1H, C11β-CH, J=7.50), 5.758 (s, 1H, C4-CH), 6.638 (d, 2H,3′,5′-aromatic CH, J=8.55 Hz) and 6.975 (d, 2H, 2′,6′-aromatic CH,J=8.55 Hz).

[0065] Preparation of17α-acetoxy-11β-[4-(N,N-dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione (11)

[0066] A mixture of trifluoroacetic anhydride (47 mL) and glacial aceticacid (19.1 mL) in methylene chloride (300 mL) was allowed to stir atroom temperature under nitrogen. After ½ hr of stirring, the mixture wascooled to 0° C. in an ice water bath and tosic acid (2.85 g, 14.98 mmol)was added. A solution of the 17α-hydroxy compound (10, 6.18 g, 13.33mmol) was added in 50 mL of methylene chloride and rinsed in withadditional CH₂Cl₂ (50 mL). After stirring for a period of 2 hr at 0° C.,examination by TLC (silica; 100% acetone in methylene chloride;neutralized with NH₄OH before developing) indicated that the reactionwas >95% complete. The reaction mixture was diluted with water (300 mL)and neutralized by careful addition of concentrated NH₄OH (75 mL). MoreNH₄OH was added to a pH of 7 as indicated by a pH paper. The productobtained was extracted by CH₂Cl₂ (3×) and the organic extracts werewashed with water (2×) and brine (1×). The combined organic extractswere dried by filtration through Na₂SO₄ and evaporated in vacuo to give7.13 g of the crude product (11). A pure material was obtained by flashcolumn chromatography (silica; 10% acetone in methylene chloride). Theimpure fractions were combined and chromatographed a second time. Thepure fractions from both chromatographic runs were combined andevaporated in vacuo, then evaporated from ether, and further dried underhigh vacuum to produce a pale yellow foam. Treatment with pentanefollowed by scratching and sonicating produced 4.13 g of 11 as a fineyellow powder in 61.3% yield; m.p. softens at 116° C.

[0067] Analysis by a reverse phase HPLC on a NOVAPAK™ C₁₈ column elutedwith 70% CH₃OH in water with 0.030% Et₃N at a flow rate of 1 mL per minand at λ=302 indicated 98.87 % purity of 11 with retention timet_(R)=6.45 min. FTIR (KBr, diffuse reflectance): v_(max) 2940, 1734,1662, 1612, 1518, 1446, 1370, 1235 and 1124 cm⁻¹. NMR (300 MHZ, CDCl₃):δ0.38 (s, 3H, C18-CH₃), 2.08 (s, 3H, C17α-OAc), 2.90 (s, 6H, —N(CH₃)₂),3.42 (s, 3H, C21-OCH₃), 4.07 and 4.33 (AB, 2H, C21-CH₂, J_(AB)=18 Hz),4.37 (s, 1H, C11β-CH), 5.80 (s, 1H, C4-CH), 6.67 (d, 2H, 3′,5′-aromaticCH, J=9 Hz) and 7.0 (d, 2H, 2′,6′-aromatic CH, J=9 Hz). MS (EI) m/z(relative intensity): 505 (M⁺, 13.5), 445 (1.1), 372 (2.7), 134 (16.2)and 121 (100). Anal. Calcd for C₃₁H₃₉NO₅: C, 73.64; H, 7.77; N, 2.77Found: C, 73.34; H, 7.74; N, 2.70.

EXAMPLE 2

[0068] This Example further illustrates an embodiment of the process ofthe present invention.

[0069] Preparation of 17α-Hydroxy-21-chloro-19-norpregna-4,9-diene-3,20-dione (12)

[0070] The cyanohydrin (1, 250 g, 0.73 mol; Davos) was suspended in 3 Lanhydrous THF (Aldrich) and stirred mechanically at room temperatureunder nitrogen. 4-(Dimethylamino)pyridine (DMAP) (22.35 g, 0.183 mol)was added as a solid. 138 mL (0.99 mol) of freshly distilledtriethylamine (TEA) from BaO was added via an addition funnel over aperiod of about five minutes, followed by the addition ofchloro(chloromethyl)dimethylsilane (115 mL, 0.876 mol). The reactionmixture was stirred overnight at ambient temperature. Thin layerchromatography (TLC)(on silica; 2% acetone in methylene chloride) showedthat all the starting material had converted to the silyl ether. Thereaction mixture was cooled to −780° C. in a dry ice/isopropanol bathand allowed to cool for about 30 minutes. Additional THF (500 mL) wasadded to rinse down the residue from the sides of the flask. Lithiumdiisopropylamide (LDA) (Acros; 2.0 M in THF/heptane, 1125 mL, 2.25 mole)was added dropwise to the reaction mixture via an addition funnel over aperiod of about 40 minutes. Upon completion of the addition, thereaction mixture was stirred for a period of 2 hours at −78° C. in a dryice bath. 6 N HCl (3400 mL, 20.4 mol) was added via the addition funnel.Upon completion of the addition, the reaction mixture was allowed towarm to room temperature as the content of the bath evaporated. Stirringwas continued overnight at room temperature under nitrogen. TLC (silica;5% acetone in methylene chloride) indicated all silyl ether hadconverted to the 21-chloro compound (12). At this point the reactionmixture was a two-phase mixture with a large amount of precipitatedmaterial. The mixture was evaporated in vacuo to remove all volatilesolvents, and chilled in an ice water bath. Ice water (about 4 L) wasadded and the mixture stirred vigorously. The precipitated product wascollected by filtration on a Buchner funnel and washed with water (6×about 500 mL). After air drying for a period of several hours, thematerial was dried in vacuo at 40° C. over KOH for two nights. Theresulting solid was transferred to an Erlenmeyer flask, suspended inpentane (about 2 L), and stirred vigorously for a period of 5-10minutes. The resulting yellow powder was collected by filtration on aBuchner funnel and washed well with additional pentane (about 1 L).After air drying for a period of about one hour, the material was driedin vacuo at 35° C. over the weekend to recover 242.96 g of a yellowpowder in 95.9% yield. This material was suitable to carry directly onto is the next reaction. m.p. 202-207° C. (191-193° C. aftercrystallization of a small portion from hot isopropanol and drying overtoluene in vacuo). FTIR (KBr, diffuse reflectance): v_(max) 3462, 2973,2949, 2880, 1729, 1643, 1598, and 1572 cm⁻¹. NMR (300 MHZ, CDCl₃) δ0.837(s, 3H, C18-CH₃), 4.345 and 4.640 (AB, 2H, C21-CH₂, J_(AB)=16.81 Hz),5.690 (s, 1H, C4-CH═). MS (EI) m/z (relative intensity): 348 (M⁺, 100),313 (33), 253 (67), 228 (54), 213 (72) and 91 (55).

[0071] Preparation of17α-Hydroxy-21-acetoxy-19-norpregna-4,9-diene-3,20-dione (4)

[0072] A suspension of the 21-chloro compound (12, 241.96 g, 0.69 mol)and KOAc (137.41 g, 1.4 mol) in freshly opened acetonitrile (6 L) wasstirred mechanically and brought to reflux under nitrogen. After 1.5hours at reflux, TLC (silica; 5% acetone in methylene chloride)indicated that the reaction had gone to completion. The reaction mixturewas allowed to cool to room temperature for a period of about 1.5 hours,following which it was evaporated in vacuo to near-dryness. Theresulting material was rinsed in to the evaporating flask with acetone(about 500 mL) and acetone was evaporated. Ice water (2 L) was added andthe flask was chilled in an ice bath. Additional water (about 3 L) wasadded and the mixture stirred vigorously for a period of about 10minutes. The precipitated product was collected by filtration on aBuchner funnel and washed with additional water (4×500 mL). The productwas allowed to air dry overnight on the Buchner funnel, and dried invacuo overnight at 35° C. over KOH to obtain 237.28 g of the crude21-OAc (4) as a pale yellow powder in 92.8% yield. The crude materialwas of sufficient purity to carry directly on to the hydrolysis. m.p.209° C. (sinters) 210-218° C. (216-222° C. after crystallization of asmall portion from boiling acetone and drying in vacuo over toluene).FTIR (KBr, diffuse reflectance): v_(max) 3473.1, 2981.9, 2903.5, 2869.0,1744.0, 1720.1, 1646.1, 1607.5 cm⁻¹. MS (EI) m/z (relative intensity):372 (M⁺, 86), 312 (75), 253 (100), 213 (93), 162 (76) and 91 (58).

[0073] Preparation of 17a-1-Dihydroxy-19-norpregna-4,9-diene-3,20-dione(5)

[0074] A suspension of the crude 21-acetate (4, 236.28 g, 0.63 mol) infreshly opened methanol (5 L) was deoxygenated by sparging with nitrogenfor 30 minutes. A 1.0 M aqueous solution of KHCO₃ was similarlydeoxygenated. The KHCO₃ solution (950 mL, 0.95 mol, 1.5×) was added tothe steroid (4), and the suspension was stirred mechanically and broughtto reflux under nitrogen. Several minutes after reaching reflux, asolution formed. After thirty minutes of holding the reaction at reflux,it was found by TLC (silica; 5% isopropanol in methylene chloride) thatall starting material had converted to a single, more polar product. Thereaction mixture was allowed to cool for a period of about one hour, andneutralized by the addition of HOAc (55 mL, 0.95 mol). The methanol wasevaporated in vacuo to recover a yellow-brown slurry. Water was added(about 4 L) and the precipitated steroid allowed to stand overnight inthe cold room (about 4° C.). The next morning, the product was collectedby filtration on a Buchner funnel, washed well with water (4×500 mL) andallowed to air dry for a period of about 7 hours. After drying in vacuoat 35° C. over KOH over the weekend, 206.93 g of a yellow-brown solidwas recovered in 100% yield. The crude diol (5) was carried directly onto the mono 3-ketal without purification. m.p. 165° C. (sinters)174-189° C. (197-201° C. after crystallization of a small portion from aminimum amount of boiling methanol and drying in vacuo at 111° C.). FTIR(KBr, diffuse reflectance): v_(max) 3518, 2943, 2864, 1713, 1655, and1598 cm⁻¹. MS (EI) m/z (relative intensity): 330 (M⁺, 100), 271 (37),253 (54), 228 (65), 213 (63), 74 (27) and 91 (43).

[0075] Preparation of3,3-Ethylenedioxy-17α,21-dihydroxy-19-norpregna-5(10),9(11)-diene-20-one(13)

[0076] The crude 17α, 21-diol (5, 204.93 g, 0.62 mol) was suspended inmethylene chloride (1 L, freshly opened) and stirred magnetically, atroom temperature under nitrogen. Triethylorthoformate (258 mL, 1.55 mol,freshly distilled) was added, followed by ethylene glycol (181 mL, 3.24mol). Tosic acid (5.9 g, 31 mmol) was added as a solid. Within severalminutes of the addition, a homogenous solution formed, and the color hadturned from amber to a dark black-green. After stirring the reactionmixture for a period of 30 minutes, it was found by TLC (silica; 50%isopropanol in methylene chloride) that all starting material hadconverted to the 3-ketal (13). The reaction mixture was quenched by theaddition of an excess of NH₄OH (about 25 mL, 0.371 mol), and themethylene chloride was evaporated in vacuo. As the last traces ofmethylene chloride were removed, the product precipitated. Water (4 L)was added to the slurry and the mixture was stirred vigorously in an icebath for one hour. The precipitated product was collected by filtrationon a Buchner funnel, washed with water (5×500 mL) and air driedovernight on the funnel. The product was then dried in vacuo overnightat 35 C. over KOH to recover 233.87 g of a yellow solid (0.62 mol,100%). The solid was suspended in ether (1.5 L), chilled in an ice bath,and stirred vigorously for a period of about 10 minutes. The resultingpowder was collected by filtration on a Buchner funnel, washed with icecold ether (3×500 mL), and allowed to air dry several hours. Inspectionof the powder and the filtrate by TLC indicated the product had beensignificantly purified from the mother liquors. The product was dried invacuo overnight at 35° C. to recover 193.45 g of the 3-ketal (13) in83.9% yield as a beige powder. The overall purified yield from thecyanohydrin (1) was 74.70%. m.p. 199-209° C. (214-216° C. aftercrystallization of a small portion from a hot methylene chloride anddrying in vacuo at 111° C. for analysis). FTIR (KBr, diffusereflectance): v_(max) 3481, 3394, 3046, 2922, 2880, 1714 and 1639 cm⁻¹.NMR (300 MHz, CDCl₃): δ0.637 (s, 3H, C18-CH₃), 3.984 (s, 4H, C3-OCH₂CH₂O), 4.292 and 4.697 (AB, 2H, C21-CH₂, J_(AB=)19.51 Hz), 5.567 (t, 1H,C11-CH═, J_(AVG)=2.40 Hz). MS (EI) m/z (relative intensity): 374 (M⁺,52), 356 (21), 297 (35), 169 (55), 99 (99) and 86 (100). Anal. Calcd.For C₂₂H₃₀ O₅.CH₂Cl₂: C, 69.93; H, 8.01. Found: C, 69.94; H, 8.03.

[0077] Preparation of3,3-Ethylenedioxy-17α-hydroxy-21-methoxy-19-norpregna-5(10),9(11)-diene-20-one (14)

[0078] A suspension of the 3-ketal-17α, 21-diol (13, 192.74 g, 0.51 mol)in anhydrous DME (1900 mL; Aldrich, Sure-Seal) was stirred mechanically,at ambient temperature, under nitrogen. proton Sponge (437 g, 2.04 mol)was added as a solid, followed by trimethyloxonium tetrafluoroborate(about 300 g, 2.03 mol). After one hour, TLC (silica; 5% isopropanol inmethylene chloride; an aliquot was diluted in water and extracted intoethyl acetate) indicated all 21-OH (13) had been converted to the21-OCH₃ compound (14). The reaction mixture was quenched by the additionof methanol. After stirring 15 minutes, solids were removed byfiltration through a sintered glass funnel and washed well with ethylacetate (3×500 mL). Both the filtrate and the solids were examined byTLC (silica; 5% isopropanol in methylene chloride). The filtrate was amixture of the 21-OCH₃ and proton Sponge, while the solids wereexclusively proton Sponge. The filtrate was evaporated in vacuo at about45° C. to recover a dark orange syrup. The orange syrup was cooled in anice bath and cold 1N HCl (4 L, chilled overnight in the cold room) wasadded with vigorous stirring. Initially, the steroid precipitated as agum, but continued stirring and scraping afforded a solid. The solid wascollected on a Buchner funnel, washed with additional 1N HCl (4×500 mL),then with water (4×500 mL) to a pH of about 6 by means of the pH paper.Examination by TLC indicated the steroid still contained a trace ofproton Sponge. The solid was again suspended in cold 1N HCl (2 L) andstirred in an ice bath for 30 minutes. The product was collected on aBuchner funnel, washed with additional cold 1N HCl (4×500 mL), thenwater (6× about 500 mL) to a pH of about 6 (pH paper). Proton Sponge waseffectively removed as evidenced by TLC. The product was allowed to airdry, and further dried overnight in vacuo at 40° C. over KOH to recover182.25 g of a pale yellow powder in 92.2% yield. The crude 21-OCH₃compound (14) was of sufficient purity to carry directly on to thesubsequent reduction. m.p. 92-94° C. (sinters) 102-107° C. (117-119° C.after purification of a small portion by flash chromatography (5%isopropanol in methylene chloride) for analysis). FTIR (KBr, diffusereflectance): v_(max) 3424, 3034, 2931, 2889, 2837, 1721, 1642, and 1472cm⁻. NMR (300 MHz, CDCl₃): δ0.653 (s, 3H, C18-CH₃), 3.441 (s, 3H,C21-OCH₃), 3.986 (s, 4H, C3-OCH₂CH₂ O), 4.225 and 4.480 (AB, 2H,C21-CH₂, J_(AB=)17.71 Hz), 5.576 (m, 1H, C11-CH═). MS (EI) m/z (relativeintensity ): 388 (M⁺, 58), 297 (49), 211 (57), 169 (54), and 99 (100).Anal. Calcd. For C₂₃H₃₂O₅.H₂O: C, 70.45; H, 8.33. Found: C, 70.42; H,8.23.

[0079] Preparation of 3,3-Ethylenedioxy-17-α,20-dihydroxy-21-methoxy-19-norpregna-5(10), 9(11)-diene (15)

[0080] To a stirred solution of 20-ketone (14, 181.25 g, 0.47 mol) inanhydrous THF (900 mL), LiAIH₄ (Aldrich, 1.0 M in ether; 235 mL, 235mmol) was added via an addition funnel over for a period ofapproximately {fraction (1/2 )}hr. Immediately upon completion of theaddition, examination by TLC (silica; 10% acetone in methylene chloride)indicated all starting material had been converted to ˜ a 3:1 mixture ofthe two 20-alcohols (7). The reaction mixture was cooled to 0° C. andquenched by a careful addition of ethyl acetate (235 mL) over a periodof about 5 minutes. The reaction mixture was further quenched by theaddition of saturated Na₂SO₄ solution (235 mL) over a period of about 5minutes. Solid Na₂SO₄ (150 g) was added and the suspension stirred onehour. precipitated aluminum salts were removed by filtration through aCelite filter cake on a sintered glass funnel. The solids were washedwith ethyl acetate (3×500 mL), and the filtrate evaporated in vacuo torecover a syrup. The flask was chilled in an ice bath and water (2 L)was added, thereby obtaining in a gummy mass. Additional water (3 L)with vigorous stirring and scraping gave no improvement. THF (1 L) wasadded to help break up the mass, but did not afford a solid precipitate.The mixture was transferred to a separatory funnel and extracted withmethylene chloride (3×2 L). The organic fractions were washed again withwater (l×), then brine (l×). The combined methylene chloride fractionswere dried by filtration through sodium sulfate, evaporated in vacuo,and dried briefly under high vacuum to recover a foam (196.9 g).Trituration with ether afforded 107.81 g of a pale yellow solid in threecrops in 59.6% yield. The solid (15) was almost exclusively the majorisomer. Only a trace of the minor isomer was present as evidenced byTLC. m.p. 142° C. (sinters) 148-153° C. (145-147° C. aftercrystallization of a small portion from a minimum amount of hot etherand a small amount of methylene chloride and drying in vacuo at 56° C.for analysis). FTIR (KBr, diffuse reflectance): v_(max) 3544, 3417,3038, 2931, 2827, 1644, 1621 cm⁻¹. NMR (300 MHz, CDCl₃): δ0.765 (s, 3H,C18-CH₃), 3.395 (s, 3H, C21-OCH₃), 3.535 (dd, 1H, C21-CH, J₁₌9.61 Hz,J₂₌3.00 Hz), 3.589 (dd, 1H, C21-CH, J₁₌9.61 Hz, J₂₌6.15 Hz), 3.895 (m,1H, C 20-CH), 3.984 (s, 4H, C3-OCH₂CH₂ O), 5.592 (m, 1H, C11-CH═). MS(EI) m/z (relative intensity): 390 (M+, 6), 372 (1), 314 (1), 297 (100)and 211 (43). Anal. Calcd for C₂₃H₃₄O₅: C, 70.74; H, 8.78. Found: C,70.62; H, 8.78.

[0081] All references cited herein, including patents, publications, andpatent application, are hereby incorporated in their entireties byreference.

[0082] While this invention has been described with an emphasis uponseveral embodiments, it will be obvious to those of ordinary skill inthe art that variations of the embodiments may be used and that it isintended that the invention may be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications encompassed within the spirit and scope of the inventionas defined by the following claims.

What is claimed is:
 1. A process for preparing a compound of formula 12

comprising treating a compound of formula 1

with chloro(chloromethyl)-dimethylsilane in the presence of a base toobtain a 17-O-(chloromethyldimethylsilyl) derivative of the compound offormula 1 and treating the 17-O-(chloromethyldimethylsilyl) derivativewith an alkali metal dialkylamide.
 2. The process of claim 1, whereinthe base is selected from the group consisting of4-dimethylaminopyridine, triethylamine, and combinations thereof.
 3. Theprocess of claim 1 or 2, wherein the 17-O-(chloromethyldimethylsilyl)derivative is treated with a lithium dialkylamide.
 4. The process of anyof claims 1-3, wherein the 17-O-(chloromethyldimethylsilyl) derivativeis treated with lithium diisopropylamide.
 5. A process for preparing acompound of formula 13

comprising selectively ketalizing the 3-ketone group of the compound offormula 5


6. The process of claim 6, wherein the selective ketalization is carriedout by treating the compound of formula 5 with ethylene glycol,triethylorthoformate, and an acid.
 7. The process of claim 5 or 6,wherein the selective ketalization is carried out at a temperature ofabout 30° C. or below.
 8. A process for preparing a compound of formula14

comprising selectively methylating the 21-hydroxyl group of the compoundof formula 13


9. The process of claim 8, wherein the selective methylation is carriedout by treating the compound of formula 13 with a trimethyloxonium salt.10. The process of claim 8 or 9, wherein the selective methylation iscarried out by treating the compound of formula 13 with trimethyloxoniumtetrafluoroborate.
 11. A process for preparing a compound of formula 15

comprising reducing the 20-ketone group of the compound of formula 14

to 20-hydroxyl group.
 12. The process of claim 11, wherein the reductionis carried out by treating the compound of formula 14 with a hydride.13. The process of claim 11 or 12, wherein the reduction is carried outby treating the compound of formula 14 with lithium aluminum hydride.14. A process for preparing a 5α,10α-compound of formula 16

comprising oxidizing a compound of formula 15


15. The process of claim 14, wherein the oxidation is carried out bytreating the compound of formula 15 with an adduct formed from ahexahaloacetone and a peroxide in the presence of a weak base.
 16. Theprocess of claim 14 or 15, wherein the oxidation is carried out bytreating the compound of formula 14 with an adduct formed fromhexafluoroacetone and hydrogen peroxide in the presence of a weak base.17. A process for preparing a compound of formula 17

comprising treating a compound of formula 16

with a Grignard reagent in the presence of a cuprous halide, quenchingthe Grignard reaction mixture with an ammonium salt, and oxidizing thecuprous halide to cupric halide.
 18. The process of claim 17, whereinthe cuprous halide is cuprous chloride.
 19. The process of claim 17 or18, wherein the Grignard reagent is prepared from4-bromo-N,N-dimethylaniline and magnesium.
 20. The process of any ofclaims 17-19, wherein the cuprous halide is oxidized by air.
 21. Aprocess for preparing a compound of formula 18

comprising deketalizing the compound of formula 17 by hydrolysis


22. The process of claim 21, wherein the deketalization is carried outby treating the compound of formula 17 with an organic acid.
 23. Theprocess of claim 21 or 22, wherein the deketalization is carried out bytreating the compound of formula 17 with acetic acid.
 24. A process forpreparing a compound of formula 10

comprising selectively oxidizing the 20-hydroxyl group of the compoundof formula 18


25. The process of claim 24, wherein the selective oxidation is carriedout by treating the compound of formula 18 with 2-iodoxybenzoic acid.26. A process for preparing a compound of formula 11

comprising (a) converting the cyanohydrin group of a compound of formula1

to a chloroacetyl group with a 17α-hydroxy group to obtain a compound offormula 12

(b) displacing the chloro group of the compound of formula 12 with anacetoxy group to obtain a compound of formula 4

(c) deacetylating the compound of formula 4 to obtain a compound offormula 5

(d) selectively ketalizing the compound of formula 5 to obtain acompound of formula 13

(e) selectively methylating the 21-hydroxyl group of the compound offormula 13 to obtain a compound of formula 14

(f) reducing the 20-ketone group of the compound of formula 14 to obtaina compound of formula 15

(g) epoxidizing the compound of the formula 15 to obtain a5α,10α-compound of formula 16

(h) introducing a N,N-dimethylaminophenyl group at the axial 11-positionvia a conjugate addition and concomitant opening the epoxide ring of thecompound of formula 16 to obtain a compound of formula 17

(i) deketalizing the compound of formula 17 to obtain a compound offormula 18

(j) selectively oxidizing the 20-hydroxyl group to a ketone group toobtain a compound of formula 10

; and (k) acetylating the compound of formula 10 to obtain the compoundof formula
 11. 27. The process of claim 26, wherein the cyanohydringroup is replaced with a chloroacetyl group with a 17α-hydroxyl group ina one-pot Silicon Nucleophilic Annelation process reaction.
 28. Theprocess of claim 26 or 27, wherein the cyanohydrin group is replaced bytreating the compound of formula 1 withchloro(chloromethyl)-dimethylsilane and a base to obtain a17-O-(chloromethyldimethylsilyl) derivative of the compound of formula 1and treating the 17-O-(chloromethyldimethylsilyl) derivative with analkali metal dialkylamide.
 29. The process of any of claims 26-28,wherein the selective ketalization of the compound of formula 5 iscarried out at a temperature below about 30° C.
 30. The process of anyof claims 26-29, wherein the epoxidation is carried out by treating thecompound of formula 15 with hexafluoroacetone and hydrogen peroxide inthe presence of a weak base.
 31. The process of any of claims 26-30including trituration of the resulting crude product of the compound offormula 16 with an ether.
 32. The process of any of claims 26-31,wherein the introduction of the N,N-dimethylaminophenyl group at the11β-position with the concomitant opening of the epoxide ring of thecompound of formula 16 is carried out by treating the compound offormula 16 with a Grignard reagent in the presence of a cuprous halide,quenching the Grignard reaction mixture with an ammonium salt, andoxidizing the cuprous halide to cupric halide.
 33. The process of any ofclaims 26-32, wherein the selective oxidation of the 20-hydroxyl groupis carried out by treating the compound of formula 18 with2-iodoxybenzoic acid.
 34. The process of any of claims 26-33, whereinthe acetylation of the compound of formula 10 is carried out by treatingthe compound with trifluoroacetic anhydride, acetic acid, andp-toluenesulfonic acid.
 35. A compound of the formula:


36. A compound of the formula:


37. A compound of the formula:


38. A compound of the formula:


39. A compound of the formula:


40. A compound of the formula:


41. A compound of the formula:


42. A process for selectively oxidizing the secondary alcohol group of acomposition containing secondary and tertiary alcohol groups comprisingtreating the composition with a haloxybenzoic acid.
 43. The process ofclaim 42, wherein said composition is an organic compound.
 44. Theprocess of claim 42 or 43, wherein the haloxybenzoic acid is2-iodoxybenzoic acid.